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1.
Proc Natl Acad Sci U S A ; 121(7): e2315069121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38315851

RESUMO

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily ("8HUM") can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis, Leishmania donovani, and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery.


Assuntos
Doenças Transmissíveis , Descoberta de Drogas , Camundongos , Animais , Interações Medicamentosas , Modelos Animais de Doenças , Sistema Enzimático do Citocromo P-450/metabolismo , Aceleração
2.
J Med Chem ; 66(15): 10413-10431, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37506194

RESUMO

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.


Assuntos
Doença de Chagas , Leishmaniose Visceral , Tripanossomicidas , Trypanosoma cruzi , Camundongos , Animais , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Complexo de Endopeptidases do Proteassoma , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Tripanossomicidas/química
3.
Infect Dis Rep ; 15(4): 360-369, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37489390

RESUMO

Mosquito-borne La Crosse virus (LACV; family: Peribunyaviridae) is the leading cause of pediatric arboviral encephalitis in the United States, with clinical cases generally centered in the Midwest and Appalachian regions. Incidence of LACV cases in Appalachian states has increased, such that the region currently represents the majority of reported LACV cases in the USA. The amount of reported LACV cases from Virginia, however, is minimal compared to neighboring states such as North Carolina, West Virginia, and Tennessee, and non-Appalachian regions of Virginia are understudied. Here we examine the hypothesis that LACV is circulating widely in Virginia, despite a low clinical case report rate, and that the virus is circulating in areas not associated with LACV disease. In this study, we screened local mammalian wildlife in northwestern counties of Virginia using passive surveillance via patients submitted to wildlife rehabilitation centers. Blood sera (527 samples; 9 species, 8 genera) collected between October 2019 and December 2022 were screened for neutralizing antibodies against LACV, indicating prior exposure to the virus. We found an overall LACV seroprevalence of 1.90% among all wild mammals examined and reveal evidence of LACV exposure in several wild species not generally associated with LACV, including eastern cottontails and red foxes, along with established reservoirs, eastern gray squirrels, although there was no serological evidence in chipmunks. These data indicate the circulation of LACV in Virginia outside of Appalachian counties, however, at a lower rate than reported for endemic areas within the state and in other states.

4.
RSC Med Chem ; 13(12): 1587-1604, 2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36561069

RESUMO

The synthesis and evaluation of twenty six new phenylurea substituted 2,4-diamino-pyrimidines against Plasmodium falciparum (Pf) 3D7 are reported. Compounds were prepared to improve both anti-malarial activity and selectivity of the series previously reported by our group. Additional properties have been determined to assess their potential as anti-malarial leads including; HepG2 cytotoxicity, solubility, permeability, and lipophilicity, as well as in vitro stability in human and rat microsomes. We also assess their inhibition profile against a diverse set of 10 human kinases. Molecular docking, cheminformatics and bioinformatics analyses were also undertaken. Compounds 40 demonstrated the best anti-malarial activity at Pf 3D7 (0.09 µM), good selectivity with respect to mammalian cytotoxicity (SI = 54) and low microsomal clearance. Quantitative structure activity relationship (QSAR) analyses point to lipophilicity being a key driver of improved anti-malarial activity. The most active compounds in the series suffered from high lipophilicity, poor aqueous solubility and low permeability. The results provide useful information to guide further chemistry iterations.

5.
Nat Commun ; 13(1): 5992, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36220877

RESUMO

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.


Assuntos
Lisina-tRNA Ligase , Mycobacterium tuberculosis , Tuberculose , Animais , Lisina-tRNA Ligase/química , Lisina-tRNA Ligase/genética , Lisina-tRNA Ligase/farmacologia , Camundongos , Mycobacterium tuberculosis/genética , Tuberculose/tratamento farmacológico
6.
Cureus ; 14(7): e27348, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36046316

RESUMO

Anxiety and depression have deleterious effects on health. Numerous studies have demonstrated the negative impact of emotions such as stress and anxiety on heart rate (HR), blood pressure (BP), and heart disease. These mood states have been linked to stroke, heart failure, diabetes, heart disease, respiratory problems, and drug abuse. Negative emotions can affect the HR and BP through the link between the nervous system and the cardiovascular system. Our study demonstrates the positive effect of classical music on HR, BP parameters, and mood states.

7.
J Relig Health ; 61(5): 4096-4118, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35534760

RESUMO

Evangelical Christianity and healthcare work are two contexts in which vocation is often an important discourse. Exploring uses, understandings and implications of vocation for evangelical medics thus offers a rich opportunity to critically interrogate vocation from two important perspectives. In addition to identifying a three-tiered construction of vocation, on macro-, meso- and micro-levels, this paper suggests that to fully understand its manifestations among a sample of English evangelical medics, a critical, Weberian-style reading is valuable. This latter conclusion resonates with those drawn by scholars who extend a critical view across constructions of medical vocation more broadly, not least given concerns regarding workplace burnout.


Assuntos
Esgotamento Profissional , Leitura , Cristianismo , Inglaterra , Humanos , Ocupações , Protestantismo
8.
Eur J Med Chem ; 238: 114421, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35594652

RESUMO

Approximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacements of the metabolically labile piperazine ring and use of plate-based arrays for quick diversity scoping. We discuss the success of these strategies within the context of this series and highlight the challenges faced in phenotypic programs when attempting to improve the pharmacokinetic profile of compounds whilst maintaining potency against the desired target.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Piperazinas/farmacologia
10.
J Med Chem ; 65(7): 5606-5624, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35303411

RESUMO

African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.


Assuntos
Trypanosoma congolense , Tripanossomíase Africana , Animais , Bovinos , Quinases Ciclina-Dependentes , Reposicionamento de Medicamentos , Trypanosoma vivax , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/veterinária
11.
Zoonoses Public Health ; 69(3): 248-253, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35156300

RESUMO

Cryptosporidium parvum is a parasitic zoonotic pathogen responsible for diarrheal illness in humans and animals worldwide. We report an investigation of a cryptosporidiosis outbreak in raccoons and wildlife rehabilitation workers at a Virginia facility. Fifteen (31%) of 49 facility personnel experienced symptoms meeting the case definition, including four laboratory-confirmed cases. Seven juvenile raccoons were reported to have diarrhoea; six had laboratory-confirmed cryptosporidiosis. Cryptosporidium parvum of the same molecular subtype (IIaA16G3R2) was identified in two human cases and six raccoons. Raccoon illness preceded human illness by 11 days, suggesting possible zoonotic transmission from raccoons to humans. This appears to be the first report of a human cryptosporidiosis outbreak associated with exposure to raccoons infected with C. parvum. Raccoons might be an under-recognized reservoir for human C. parvum infections. Further study is needed to explore the prevalence of cryptosporidial species in raccoons and their role as a wildlife reservoir.


Assuntos
Criptosporidiose , Cryptosporidium parvum , Cryptosporidium , Animais , Animais Selvagens , Criptosporidiose/epidemiologia , Criptosporidiose/parasitologia , Guaxinins/parasitologia , Virginia
12.
J Med Chem ; 65(1): 409-423, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34910486

RESUMO

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Benzofuranos/farmacologia , Palmitoil-CoA Hidrolase/antagonistas & inibidores , Piperidinas/farmacologia , Policetídeo Sintases/antagonistas & inibidores , Benzofuranos/síntese química , Cardiotoxicidade , Descoberta de Drogas , Canal de Potássio ERG1 , Coração/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidinas/síntese química , Relação Estrutura-Atividade
13.
Bioorg Med Chem ; 46: 116348, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34479064

RESUMO

Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC50 of 0.66 µM at the 3D7 strain and a selectivity (SI) of ~ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD7.4 (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.


Assuntos
Antimaláricos/farmacologia , Quimioinformática , Diaminas/farmacologia , Inibidores Enzimáticos/farmacologia , Fosfotransferases/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Diaminas/síntese química , Diaminas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Hep G2 , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Fosfotransferases/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
14.
Breastfeed Med ; 16(9): 717-724, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33872065

RESUMO

Background: Pasteurized donor human milk (PDHM) supplementation for healthy infants is an emerging practice. Little is known about demographics or breastfeeding outcomes for dyads whose mothers choose PDHM versus formula. Research Aims: To identify relationships between in-hospital supplementation choice and (1) dyad characteristics and breastfeeding intent, and (2) breastfeeding outcomes at 1 month. Materials and Methods: This exploratory prospective cohort study surveyed healthy dyads requiring medically indicated supplementation. Participants completed questionnaires including demographics, breastfeeding intent, and self-efficacy during hospitalization, and self-efficacy and lactation outcomes at 1 month. Results: Of 39 participants, 24 (62%) supplemented with formula and 15 (38%) with PDHM. Formula dyads were more likely than PDHM dyads to have a delivery body mass index (BMI) ≥30 kg/m2 (58% versus 20%, p = 0.02), and less likely to have attained greater than a college degree (33% versus 7%, p = 0.02); formula dyads also reported lower breastfeeding intent scores (12.0 versus 15.5, p = 0.002). Breastfeeding self-efficacy scores were similar but decreased for both groups over 1 month. At 1 month, mothers who chose formula were more likely to continue to provide breast milk to their infants (84% versus 72%). Direct breastfeeding rates were similar (72% versus 68%); of participants directly breastfeeding at 1 month, PDHM dyads were 1.5 times more likely to provide maternal expressed milk. Conclusions: Differences in maternal education, BMI, and breastfeeding intent were found between feeding groups. Results suggest an association between PDHM choice and initial breastfeeding intent and breastfeeding self-efficacy and provision of maternal expressed milk at 1 month.


Assuntos
Aleitamento Materno , Leite Humano , Suplementos Nutricionais , Feminino , Hospitais , Humanos , Lactente , Estudos Prospectivos
15.
J Med Chem ; 64(9): 5905-5930, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33904304

RESUMO

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.


Assuntos
Desenho de Fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Proteínas de Protozoários/metabolismo , Animais , Antiprotozoários/química , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Sítios de Ligação , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/metabolismo , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Camundongos , Simulação de Dinâmica Molecular , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Proteínas de Protozoários/química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Solubilidade , Relação Estrutura-Atividade
16.
Molecules ; 26(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807614

RESUMO

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CLint) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min-1 kg-1 ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min-1 kg-1 ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CLH) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min-1 kg-1 ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min-1 kg-1 ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CLH is much slower than CLint. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism.


Assuntos
Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/farmacocinética , Proteínas Sanguíneas/metabolismo , Canabinoides/química , Canabinoides/farmacocinética , Células Cultivadas , Simulação por Computador , Estabilidade de Medicamentos , Meia-Vida , Hepatócitos/efeitos dos fármacos , Humanos , Drogas Ilícitas , Inativação Metabólica , Indazóis/química , Indazóis/farmacocinética , Indóis/química , Microssomos Hepáticos/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Valina/análogos & derivados , Valina/química , Valina/farmacocinética
17.
ACS Omega ; 6(3): 2284-2311, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33521468

RESUMO

With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-à-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles (1-2) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis. The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29, with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to 29, and under replicating conditions, 29 demonstrated bactericidal activity against M. tuberculosis. Unfortunately, compound 29 had no efficacy in an acute model of TB infection; this was most likely due to the in vivo exposure remaining above the minimal inhibitory concentration for only a limited time.

18.
Eur J Med Chem ; 207: 112849, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007723

RESUMO

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/química , Nitroimidazóis/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Camundongos , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/fisiologia
19.
J Med Chem ; 63(17): 9523-9539, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32663005

RESUMO

Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26 000-65 000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy, and unsuitable dosing options. The need for new treatments is urgent and led to a collaboration between the Drugs for Neglected Diseases initiative (DNDi), GlaxoSmithKline (GSK), and the University of Dundee. An 8-hydroxynaphthyridine was identified as a start point, and an early compound demonstrated weak efficacy in a mouse model of VL but was hampered by glucuronidation. Efforts to address this led to the development of compounds with improved in vitro profiles, but these were poorly tolerated in vivo. Investigation of the mode of action (MoA) demonstrated that activity was driven by sequestration of divalent metal cations, a mechanism which was likely to drive the poor tolerability. This highlights the importance of investigating MoA and pharmacokinetics at an early stage for phenotypically active series.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Desenho de Fármacos , Leishmania/efeitos dos fármacos , Naftiridinas/química , Naftiridinas/farmacologia , Animais , Concentração Inibidora 50 , Camundongos , Solubilidade , Relação Estrutura-Atividade , Água/química
20.
J Med Chem ; 63(6): 3066-3089, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32134269

RESUMO

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments. In this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a library of compounds against T. cruzi. The compound series was optimized to the level where it had satisfactory pharmacokinetics to allow an efficacy study in a mouse model of Chagas disease. We were able to demonstrate efficacy in this model, although further work is required to improve the potency and selectivity of this series.


Assuntos
Doença de Chagas/tratamento farmacológico , Quinazolinonas/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Descoberta de Drogas , Feminino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Estudo de Prova de Conceito , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Ratos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacocinética
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